Mitogen-activated protein (MAP) kinases is a kind of serine-threonine kinase which transfers a γ-phosphate group of adenosine triphosphoric acid (ATP) to a hydroxyl of specific serine or threonine constituting a protein, and participates in various cell responses against extra-cellular signals. The p38 MAP kinase is a protein with about 38 kDa which is subjected to cloning as a homologue of a MAP kinase.
The p38 MAP kinase is activated by an inflammatory cytokines such as tumor necrosis factor α (TNF-α), inter-leukin 1 (IL-1), etc., or by stress stimulation such as ultraviolet ray irradiation, etc. Also, it has been clarified that the p38 MAP kinase phosphorylates various transcription factor groups and kinase groups as substrates, these transcription factor groups and kinase groups are activated by the p38 MAP kinase, so that they contribute to progress in transcription, control after the transcription (stabilization of mRNA and progress of translation of protein) and stabilization of proteins, etc. with regard to various proteins which participate in inflammatory reaction such as inflammatory cytokines, etc. From these facts, it has been considered that the p38 MAP kinase deeply involves in various inflammatory reactions, etc. through control of production and/or signal transduction of inflammatory cytokines so that there is a high probability that an inhibitor of the p38 MAP kinase is to be an agent for treatment of inflammatory diseases and the like.
As an inhibitor of p38 MAP kinases, imidazole derivatives are known in (Patent Literature 1), 1,3-thiazole derivatives in (Patent Literature 2), 1,3-thiazole derivatives and 1,3-oxazole derivatives in (Patent Literature 3), imidazole derivatives, pyrrole derivatives, furan derivatives, 3-pyrazolin-5-one derivatives, pyrazole derivatives and thiophene derivatives, etc. in (Non-patent Literature 1), and 4-imidazolin-2-one compound in (Patent Literature 4), respectively.
[Patent Literature 1] JP 2000-503304-A
[Patent Literature 2] JP 2001-114690-A
[Patent Literature 3] JP 2001-114779-A
[Patent Literature 4] WO 03/035638
[Non-patent Literature 1] Expert Opinion on Therapeutic Patents, 2000, 10(1), p. 25-37